Anti-inflammatory effects of natural flavonoid diosmetin in IL-4 and LPS-induced macrophage activation and atopic dermatitis model

Diosmetin, a citrus flavonoid, has a variety of therapeutic properties such as antibacterial, anti-inflammatory and antioxidant effects. However, the effect of diosmetin on atopic dermatitis (AD) development has not been reported. This study thus aims to investigate whether diosmetin possesses inhibitory effects on AD development. A dinitrochlorobenzene (DNCB)-induced AD mouse model was used to evaluate the effects of diosmetin on AD development. Treatment with diosmetin significantly reduced the dermatitis score, thickness of epidermis and dermis and number of mast cells in comparison with the untreated group. Furthermore, immunohistochemical analysis using an anti-F4/80 antibody demonstrated that diosmetin significantly suppressed macrophage infiltration into the AD lesion. It was observed that the levels of pro-inflammatory cytokines (TNF-α, IL-4 and IL-1β) in skin lesion decreased in response to treatment with diosmetin. In addition, the anti-inflammatory effect of diosmetin was evaluated in LPS- or IL-4-induced a mouse macrophage cell line (raw 264.7). Diosmetin inhibited the production of nitric oxide and decreased the expression of inducible nitric oxide synthase (iNOS). Diosmetin not only suppressed the phosphorylation of MAP kinase (ERK 1/2, p38 and JNK) but the activation of JAK/STAT signaling. The mRNA analysis demonstrated that diosmetin also reduced the level of inflammatory cytokines such as IL-1β and IL-6. Collectively, these results demonstrate that diosmetin exhibits the inhibitory effect on AD, suggesting that diosmetin may be a potential therapeutic agent for this atopic disorder.